This is a 371 of International Application Serial No. PCT/EP98/08291, filed Dec. 17, 1998.
The present invention relates to phthalazine derivatives, to pharmaceutical compositions comprising them and to their use as phosphodiesterase 4 inhibitors.
Phosphodiesterases are a family of isoenzymes which constitutes the basis of the main mechanism of cAMP (cyclic adenosine-3xe2x80x2,5xe2x80x2-monophosphate) hydrolytic inactivation. cAMP has been shown to be the second messenger mediating the biologic response to many hormones, neurotransmitters and drugs [Krebs Endocrinology Proceedings of the 4th International Congress Excerpta Medica, 17-29, 1973]. When the suitable agonist binds the cell surface, the adenylated cyclase activates and turns Mg2+-ATP into cAMP. cAMP modulates the activity of the majority, if not of all, of the cells contributing to the pathophysiology of various respiratory diseases both of allergic origin and not. It follows that an increase of CAMP concentration yields beneficial effects such as airway smooth muscle relaxation, inhibition of the mast cell mediator release (basophil granulose cells), suppression of the neutrophil and basophil degranulation, inhibition of the monocyte and macrophage activation. Thus, compounds capable of activating adenylate cyclase or of inhibiting phosphodiesterases could suppress the undesired activation of the airway smooth muscle and of a great number of inflammatory cells.
In the phosphodiesterase family there is a distinct group of isoenzymes, phosphodiesterases 4 (hereinafter PDE 4), specific for the hydrolysis of the airway smooth muscle and inflammatory cells cAMP (Torphy, xe2x80x9cPhosphodiesterase Isoenzymes: Potential Targets for Novel Anti-asthmatic Agentsxe2x80x9d in New Drugs for Asthma, Barnes, ed. IBC Technical Services Ltd, 1989). Studies carried out on this enzyme show that its inhibition yields not only airway smooth muscle relaxation, but also mastocyte suppression, basophil and neutrophil degranulation, thus inhibiting monocyte activation and neutrophil activation. Furthermore, the PDE 4 inhibitors activity is markedly improved when the adenylated cyclase activity of the target cells is enhanced by endogenous hormones, as the case in vivo. Thus, PDE 4 inhibitors should be effective in the therapy of asthma. Such compounds would offer a unique approach to the therapy of various respiratory diseases both of allergic origin and not, and possess significant therapeutic advantages over the current therapy.
The excessive or irregular production of the tumor necrosis factor (hereinafter TNFxcex1), a cytokine with pro-inflammatory activity produced by various kind of cells, affects the mediation or the exacerbation of many pathologies such as, for example, the adult respiratory disease syndrome (ARDS) and the chronic pulmonary inflammatory disease. Therefore, compounds able to control the negative effects of TNFxcex1, i.e. the inhibitors of this cytokine, are to be considered useful against many pathologies.
The patent application EP-0 722 936 (in the name of Eisai) claims, inter alia, compounds of formula 
wherein n=0-4; R1, is an optionally substituted lower alkoxy or cycloalkyl, or a xe2x80x94OR9 group wherein R9 is an optionally substituted arylalkyl group; Y is xe2x80x94CBxe2x95x90 wherein B is an optionally substituted heteroarylalkyl group or xe2x80x94NR7R8 wherein one of R7, and R8 may be H and the other an optionally substituted heteroarylalkyl group; A is hydrogen or a halogen atom, optionally mono- or bi-substituted amino group, optionally substituted aryl, heteroaryl or heteroarylalkyl group. Among the groups optionally substituting the above mentioned residues halogen atoms are listed. Such compounds are said to be active as cGMP-PDE inhibitors, i.e. PDE 5, a phosphodiesterase acting by a cGMP-dependent mechanism and whose field of action is markedly cardiovascular (Schudt C. et al., Phosphodiesterase Inhibitors, Academic Press).
The patent application EP0 498 723 (in the name of Roussel Uclaf) discloses, inter alia, compounds of formula 
wherein R2b and R3b are hydrogen, hydroxy, alkyl, cycloalkyl, acyloxy, at least one but no more then two of A1b, A2b, A3b and A4b are a nitrogen atom and at least one of them is a methyne radical substituted by the xe2x80x94R5xe2x80x94YB group wherein R5 is a divalent alkylene radical, and YB represents the radical xe2x80x94Y1Bxe2x80x94Bxe2x80x94Y2B wherein Y1B is a monocyclic aryl optionally containing nitrogen, B is a single bond and Y2B is hydrogen or halogen. These compounds are said to be effective for the treatment of arterial hypertension, heart and renal failure and for the prevention of restenosis after angioplasty.
The patent application EP-0 017 411 (in the name of Pfizer) claims phthalazines of formula 
wherein R1 is lower alkyl; Y is xe2x80x94(CH2)mxe2x80x94Z wherein m is 1 or 2, and Z is carbamoyloxy, carbonylamino, sulfamoyl, ureido, amino-sulfamoyl, carboxamino substituted on the terminal portion by a (C3-7)cycloalkyl. These compounds are said to be phosphodiesterase inhibitors and to have a cardiac muscle stimulating activity, thus their action does not relate to PDE 4. The U.S. Pat. No. 3,274,185 (in the name of Messengill) describes, inter alia, phthalazines of formula 
wherein Y and Y1 are lower alkoxy; Z is phenyl optionally substituted by halogen or benzyl; and R is hydrogen. These phthalazines are endowed with sedative and hypertensive activity, without an explicit mechanism of action.
The U.S. Pat. No. 3,813,384 (in the name of Asta-Werke) illustrates, inter alia, benzylphthalazinones of formula 
wherein R1 and R2 are lower alkoxy or halogen; X is an optionally branched alkylene chain; m and n are 1-3; p is 0 or 1; and the 
group is a C3-8 mono-, bi- or tricyclic residue containing one or two nitrogen atom(s). Such compounds have a hystaminolytic action and are useful, for example, in the treatment of asthma.
The patent application NL 8005411 (in the name of Mitsubishi Yuka) describes phthalazines of formula 
wherein X is O or NH, R1, R2 and R3 are, inter alia, (C1-5)alkyl, (C1-5)alkoxy, halogen or CF3; n, m and p are 0-3. The use of these compounds is as platelet aggregation inhibitors.
The patent application JP-56061365 (in the name of Showa Denko) describes phthalazinones of formula 
wherein, inter alia, R is halogen and n is 1-3, as vasodilators and anti-ulcer agents.
The patent application WO 97/40020 (in the name of Schering AG) illustrates, inter alia, compounds of formula 
wherein R1 and R2 are H, nitro, halogen, amino, lower alkoxy or xe2x80x94CF3; R4 is H or lower alkyl; R5 is lower alkyl. These compounds are uncompetitive antagonists of excitatory aminoacids. The patent application WO097/48697 (in the name of Rhone Poulenc Rorer), published on Dec. 24, 1997, disloses, inter alia, compounds of formula 
wherein A is an azaheterocycle and B an azaheteroaryl ring or an optionally halo-substituted benzene ring; Z1 is a bond or an oxygen atom; R1 is H or lower alkyl optionally substituted by halogen atom(s); A1 is a bond or a C1-6 alkylene optionally substituted by aryl, cycloalkyl or heteroaryl; R2 may be H, aryl heteroaryl; R3 may be aryl, heteroaryl, aryl-methoxy, heteroaryl-methoxy; n and m are alternatively 0 or 1. The aryl and heteroaryl moieties may be substituted by halogen atoms. These compounds are PDE 4 and TNF inhibitors.
Therefore the present invention relates to compounds of formula I 
wherein B is methylene, ethylene, amino, CONH or a bond;
Cy is phenyl or a 5- or 6-membered heterocycle containing from 1 to 3 nitrogen atom(s), being both the residues optionally substituted by one or more substituent(s);
R is H, phenyl or a (C1-4)alkyl group optionally substituted by an aromatic or hydrogenated ring containing from 5 to 7 members;
R1 is a (C1-6)alkyl or polyfluoro(C1-6)alkyl group;
R2 is aryl aryl-(C1-10)alkyl or a (C4-7)cycloalkyl group optionally containing an oxygen atom and optionally substituted by a polar substituent;
and the Nxe2x86x92O derivatives and pharmaceutically acceptable salts thereof;
with the proviso that when R is H, R2 is not aryl-methyl.
The proviso is due to avoid the overlap with the patent application WO97/48697 (in the name of Rhone Poulenc Rorer) said above.
The compounds of formula I may have an asymmetric centre and thus may be in the form of stereoisomers. The objects of the present invention are the compounds of formula I in the form of stereoisomeric mixtures as well as single stereoisomers.
The compounds of formula I are active as PDE 4 and TNFxcex1 inhibitors, and are thus used as therapeutic agents in allergic and inflammatory pathologies such as, for example, emphysema, chronic bronchitis, asthma and allergic rhinitis.
As for 5- or 6-membered heterocycle it is meant pyrrole, imidazole, pyrazole, pyrrolidine, pyrroline, imidazoline, imidazolidine, pymzolidine, pyrazoline, pyridine, pyrazine, pyrimidine, pyridazine, piperazine, piperidine, triazine, and the like, preferably pyridine and piperidine. The substituents optionally present on Cy may be keto, nitro, carboxy, halogen, this term embracing a fluorine, chlorine, bromine or iodine atom, chlorine being the preferred substituent.
Specific examples of alkyl groups are methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, tert-butyl, n-pentyl, 1-methyl-butyl, 2-ethyl-propyl, 3-ethyl-utyl, 3-ethyl-tyl, n-exyl and the like. As for (C5-7) cycloalkyl group it is meant cyclopentyl, cyclohexyl and cycloheptyl, and when it contains an oxygen atom it is meant, for example, tetrahydrofuran or tetrahydropyran, while aryl and aryl-(C1-10) mean a ring or a C6-10 aromatic system such as, for example, phenyl, benzyl, phenethyl, phenyl-pentyl, naphthyl, indanyl, indanyl-pentyl and the like. For xe2x80x9cpolar substituentxe2x80x9d it is meant those groups constituted by atoms with different electronegativity thereby a dipole is created, such as, for example, hydroxy or keto groups, are meant.
The Nxe2x86x92O groups optionally preset in number of one or more may regard both the nitrogen atoms of the phthalazine ring, and the ones on the substituent Cy.
Pharmaceutically acceptable salts of the compounds of formula I are those with organic and inorganic acids, such as, for example, hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, acetic, benzoic, maleic, fumaric, succinic, tartaric, citric, aspartic, methansulfonic, 3,7-di-tert.butylnaphthalen-1,5-disulfonic (dibudinic acid).
Preferred compounds of formula I are those wherein B is methylene or amino; Cy is phenyl or a 5- or 6membered heterocycle containing from 1 to 3 nitrogen atom(s), both the residues being optionally substituted by 1 or 2 halogen(s); R is H, phenyl or a (C1-4)alkyl group optionally substituted by an aromatic or hydrogenated ring containing 5-7 members; R1 is a (C1-6)alkyl or polyfluoro(C1-6)alkyl group; R2 is a (C4-7)cycloalkyl group optionally containing an oxygen atom and optionally substituted by a polar substituent; and the Nxe2x86x92O derivatives and pharmaceutically acceptable salts thereof.
More preferred compounds of formula I are those wherein B is methylene; Cy is phenyl or a 6-membered heterocycle containing 1 nitrogen atom, being both the residue substituted by 1 or 2 chlorine atom(s); R is phenyl or a (C1-4)alkyl group optionally substituted by a 5-7 members aromatic or hydrogenated ring; R1 is a (C1-6)alkyl, polyfluoro(C1-6)-alkyl group; R2 is a (C4-7)-cycloalkyl group optionally containing an oxygen atom and optionally substituted by a polar substituent; and the Nxe2x86x92O derivatives and the pharmaceutically acceptable salts thereof.
The synthesis of the compounds of formula I proceeds according to methods known to the skilled in the art. For example, a benzaldehyde of formula II 
wherein R1 and R2 are as defined above, is oxidized, for example with potassium permanganate and tetrabutylammonitun bromide, to give an acid of formula III 
wherein R1 and R2 are as defined above, which, for example by treatment with thionyl chloride, is turned into the corresponding acyl halide of formula IV 
wherein R1 and R2 are as defined above and X is chlorine or bromine. This compound is reacted with diethylamine in an at least equimolar amount to give a benzamide of formula V 
wherein R1 and R2 are as defined, which reacted with dimethylformamide in the presence of a strong organic base such as, for example, n-butyl-lithium, tert butyl-lithium, sec-butyl-lithium, optionally in the presence of a binding agent such as, for example, tetramethylethylendiamine, yields a compound of formula VIa 
wherein R1 and R2 are as defined above, and R1 is hydrogen.
When a compound of formula I wherein R=H is desired, the compound of formula VIa is reacted with an equimolar amount of tert-butylcarbazole to give a compound of formula VIIa 
wherein R1, R1 and R2 are as defined above, and Rxe2x80x2 is a protecting group of the carboxy moiety such as, for example, tert-butyl.
Instead, when a compound of formula I wherein R is other than hydrogen is desired, the compound of formula VIa is treated with RII-magnesium halide, for example, chloride, or RII-lithium, wherein RII is phenyl or a (C1-4)alkyl group optionally substituted by an aromatic or hydrogenated ring having from 5 to 7 members, to give a compound of formula XIII 
wherein RII, R1 and R2 are as defined above. The compound of formula XIII is treated with a suitable oxidising agent such as, for example, pyridinium-chloro chromate, and yields a compound of formula VIb 
wherein R1, R2 and RII are as defined above, which is treated with an equimolar amount of tert.butylcarbazole to give a compound of formula VIIb, which differs from the compound VIIa in that R has the meanings of formula I but hydrogen.
The compound of formula VIIa or VIIb is reacted with trifluoroacetic acid to give the phthalazinone of formula VIII 
wherein R, R1 and R2 are as defined above. This phthalazinone is reacted with a halogenating agent such as, for example, phosphoryl chloride, to give the phthalazine of formula IX 
wherein R, R1 and R2 are as defined above, and Xxe2x80x2 is a halogen atom.
Alternatively, the compound of formula VIII may be directly obtained from the compound of formula VIa or VIb by treatment with hydrazine in acetic acid.
The compound of formula IX yields a compound of formula I by treatment with a compound of formula XIV
Cyxe2x80x94Bxe2x80x2xe2x80x94Yxe2x80x83xe2x80x83(XIV)
wherein Cy is as defined above, Bxe2x80x2 is methylene, ethylene, amino or a bond and Y is hydrogen, halogen.
When a compound of formula I wherein B is CONH is desired, the compound IX is reacted with carbon monoxide and methanol in the presence of a catalyst such as metal palladium or nickel, to give a compound of formula XV 
wherein R, R1, and R2 are as defined above, which is then turned into the desired compound of formula I through methods known to those skilled in the art, for example by reaction with an aryl-amine in the presence of bases.
Alternatively, the compounds of formula I may be synthesized by treatment of a compound of formula VIa or VIb with acetic acid in acidic medium to give a compound of formula X 
wherein R and R1 are as defined above, and Rxe2x80x22 has the meaning of R2 listed above plus hydrogen, which is reacted with hydrazine to give a phthalazinone of formula XI 
wherein R, R1 and Rxe2x80x22 are as defined above. When Rxe2x80x22 is hydrogen this compound is treated with the due compound of formula XIIa or XIIb
R2OSO2CH3xe2x80x83xe2x80x83(XIIa)
R2Xxe2x80x83xe2x80x83(XIIb)
wherein R2 and X are as defined above to give a compound of formula VIII as described above.
Another alternative is for the compounds of formula I wherein B is other than amino, which may be yielded starting from the acid of formula III reacted with formaldehyde/HCl which forms a compound of formula XVI 
wherein R1 and R2 are as defined above. This compound is oxidized, for example with benzoyl peroxide/N-bromo-succinimide, then hydrolyzed to give a compound of formula XVII 
wherein R1 and R2 are as defined above, which with a halogenidric acid and triphenylphosphine gives a compound of formula XVIII 
wherein R1 and R2 are as defined above, which treated with an aldehyde of formula XIX
Cyxe2x80x94Bxe2x80x3xe2x80x94CHOxe2x80x83xe2x80x83(XIX)
wherein Cy is as defined above and Bxe2x80x3 is methylene or is absent, in the presence of an organic base such as, for example, triethylamine, gives a compound of formula XX 
wherein R1, R2, Bxe2x80x3 and Cy are as defined above. This is reacted with hydrazine to give a compound of formula XXI 
wherein R1, R2, and Cy are as defined above and B is other than amino, which is treated with a halogenating agent, such as phosphoryl chloride or bromide, to give a compound of formula XXII 
wherein R1, R2, X and Cy are as defined above and B is other than amino. This compound is subjected to a coupling reaction with the suitable metallorganic derivative in the presence of a catalyst, for example, a palladium-based catalyst, or to a nucleophilic substitution which gives a compound of formula I wherein B is other than amino.
A choice for having a compound of formula I wherein R1 is a polyfluoro(C1-6)alkyl group consists in treating a compound of formula XXIII 
wherein Rxe2x80x21, is hydrogen, with bases, for example a carbonate or bicarbonate, and a polyfluoro(C1-6)alkyl-chloride, -bromide or -iodide at 70-75xc2x0 C. The compound of formula XXIII may be obtained from a compound of formula I wherein R1 is (C1-6)alkyl for example by treatment with sodium p-thiochresolate in the presence of a base such as dimethylformamide.
The synthesis of the N-oxides of the compounds of formula I is effected by treating the compounds of formula I with peracids such as, for example m-chloroperbenzoic acid.
The preparation of the salts of the compounds of formula I is effected by conventional methods.
The compounds of formula I are PDE 4 inhibitors as resultant from the in vitro enzymatic inhibition activity tests (Example 67), without any effect on PDE 3 and PDE 5 (Example 69). Moreover they are able to inhibit the TNFxcex1 release (Example 68). Companions with the following compounds have been carried out: 6,7-dimethoxy-4-(pyridin-4-yl-methyl)-2H-phthalazin-1-one (reference 1) and 6,7-dimethoxy-4-(piperidin-4yl-methyl)-2H-phthalazin-1-one (reference 2) embraced by the general formula of the patent application EP-0 722 936 (in the name of Eisai) just cited above, chosen in view of the structural affinity with the compounds of the invention. The reference compounds, though chemically alike, did not show to be active on PDE 4.
It is apparent how these receptorial selectivity and specificity features joined with the lack of activity on the cardiovascular system make the compounds of formula I particularly suitable for the treatment of the pathologies involving PDE 4 and TNFxcex1 even if in the present context the interest is specifically focused on the respiratory pathologies. Especially the compounds of the invention are useful in the treatment of allergic and inflammatory diseases and above all in the therapy of emphysema, of chronic obstructive pulmonary disease and chronic bronchitis in particular, of asthma and allergic rhinitis.
The therapeutical dosage shall generally be comprised between 0.1 and 1,000 mg a day and between 1 and 100 mg by oral route for a single administration.
A further object of the present invention are the pharmaceutical compositions comprising a therapeutically effective amount of the compounds of formula I or of the pharmaceutically acceptable salts thereof in admixture with a suitable carrier.
The pharmaceutical compositions object of the invention may be liquid, suitable for enteral or parenteral administration, and, preferably, solid such as tablets, capsules, granulates, suitable for oral admin on, or in a form suitable for the transdermic or inhalatory administration. The preparation of the pharmaceutical compositions object of the invention may be effected according to common techniques.